tbuckley/cabot-search huggingface dataset:
Human biological monitoring of nanoparticles, a new way to investigate potential causal links between exposure to nanoparticles and lung diseases?
Authors: V. Forest, J. Pourchez
Journal: Pulmonology (2022)

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not.The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Human biological monitoring of nanoparticles, a newway to investigate potential causal links between exposure to nanoparticles and lung diseases?V. Forest, J. Pourchez
Chronic obstructive pulmonary disease exacerbations' management in Portuguese hospitals – EvaluateCOPDpt, a multicentre, observational, prospective study
Authors: J. Moita, U. Brito, C. Rodrigues, L. Ferreira, J.R. Vieira, A. Catarino, A. Morais, V. Hespanhol, C.R. Cordeiro
Journal: Pulmonology (2022)

In order to improve the quality of chronic obstructive pulmonary disease (COPD) patients' care, better knowledge of clinical practice and the factors associated with patient outcomes are needed. This study aimed to evaluate the relation between clinical practice and the outcomes of patients admitted for COPD exacerbations in Portuguese hospitals. Observational, multicentre, prospective study with a 60-days follow-up period, in 11 hospitals, including patients aged ≥ 30 years, admitted to hospital for at least 24 hours due to an acute exacerbation of COPD. Demographic and clinical data were collected, including sex, age, smoking habits, hospitalisations, pulmonary function, comorbidities, COPD symptoms, and treatment. Sixty days after discharge, COPD exacerbations management, outcome measures, and readmission data were evaluated through a structured phone follow-up interview. 196 patients were included (85.7% male, mean age 71.2 years), the majority admitted through the emergency service. Ex-smokers and current smokers accounted for 51% and 36%, respectively. On admission, 72.4% were on LAMA, 54.6% on LABA, and 45.5% were on LABA/LAMA. Inhaled corticosteroids (ICS) were used in 37.3% and systemic steroids (SCS) in 10.3%. 35.7 % had had at least one exacerbation, with hospitalisation, in the previous year. There was no spirometry data for 23.2%. On hospitalisation, 98.5% of patients were treated with oxygen and 38.3% with non-invasive ventilation. Additionally, 93.4% used SCS and 60.2% ICS. Antibiotics were administered to 85.2%. 95.4% of patients were discharged; 9 died, 5 of whom had a COPD-related death. The median length of stay was 12 days for discharged patients and 33 days for patients who died. At discharge, 79.1% were prescribed with LAMA, 63.6% SCS, 61.5% LABA and 55.6% LAMA+LABA. 26,2% were prescribed with ICS+LABA+LAMA. At follow-up, 44.4% had a scheduled medical appointment within the 60 days after being discharged, and 28.3% were later readmitted due to exacerbation, of whom 52.8% were hospitalised. The severity of COPD, particularly in exacerbations, is directly related to impaired lung function and quality of life, mortality, and significant health system costs. Knowledge about COPD exacerbations' management in acute hospital admissions in Portugal may help stimulate a national discussion and review of existing data to engage clinicians, policymakers, managers, and patients, raising awareness and promoting action on COPD.
Abstract A025: Profiling tumor infiltrating immune cells for better understanding tumor status and better response to therapeutic strategy in soft tissue sarcomas
Authors: Eun-Young Lee, Hyun Guy Kang, June Hyuk Kim, Jong Woong Park, Seog Yun Park, Tak Yun, Hye Jin You
Journal: Clinical Cancer Research (2022)

Abstract The tumor microenvironment is closely associated with tumor development and progression, which is made up of tumor cells, blood vessels, immune cells, fibroblast, and so on. Especially, immune cells within tumor microenvironments have been attracted in clinicians and researchers for unexpected therapeutic responses. Even in sarcoma, which is rare, and heterogenous leading to few options for cure, immune therapy has been tried and shown to be promising. However, the information of immune cells within soft tissue sarcomas were limited, which mostly have been obtained and characterized by omics-based analyses or tissue staining such as immunohistochemistry. Here, we established platform to profile tumor infiltrating immune cells by flow cytometry. About thirty sarcoma tissues were obtained, in which tumor infiltrating immune cells were profiled. The profiled data were confirmed by immunohistochemistry for correlation. It was shown that infiltrated leukocytes and CD3+ T cells were remarkably increased, whereas NKT and CD4+ T cells were decreased in tumor tissues compared to adjacent normal tissues. M1 macrophage was also increased in tumor tissues. High CD3+ T cell population was positively correlated with CD8+ T cells and PD1+ CD8+ T cell population. Especially, PD1+CD8+ T cells are usually expressed exhaustion-related conditions and low levels of cytotoxic immune cells. This study provides resources to understand immune cell population of soft tissue sarcoma, and will gain a fundamental matrix to study immunotherapy. These studies might show the possibility to find potential prognostic and immunotherapeutic targets. Citation Format: Eun-Young Lee, Hyun Guy Kang, June Hyuk Kim, Jong Woong Park, Seog Yun Park, Tak Yun, Hye Jin You. Profiling tumor infiltrating immune cells for better understanding tumor status and better response to therapeutic strategy in soft tissue sarcomas [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A025.
Abstract A039: IGFBP5 is induced by tumor-suppressive naïve stromal cells and regulates GAS2-associated apoptosis in rhabdomyosarcoma
Authors: Monika Ehnman, Karim Katkhada, Liu Zhen Meng, Yue Zhang, Binbin Zhao, Shanlin Tong, Aditi Kallai, Arne Östman, Nick Tobin
Journal: Clinical Cancer Research (2022)

Abstract Stromal cells can have either suppressive or stimulatory effects on tumor progression. However, this diverse collection of cells is still poorly characterized in soft-tissue sarcomas. Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood with molecular features of skeletal muscle differentiation. In this study, we explored tumor growth-regulatory signaling between differentially educated non-malignant mesenchymal stromal cells and malignant tumor cells in RMS. Xenograft experiments in mice were designed to provide functional evidence for alterations in tumor behavior linked to tumor-associated stromal cells. Molecular characterization was performed on the Clariom D platform, by gene set enrichment analysis, cell culture validation of deregulated genes, and finally, by clinicopathological validation in a discovery cohort (N=101) and a validation cohort (N=147). The results revealed transient tumor growth-suppressive paracrine effects of naïve orthotopic stromal cells derived from skeletal muscle. These effects were easily abolished if the stromal cells were pre-exposed to RMS cells, either short-term in vitro, or long-term in hindlimb muscle in vivo. Explorative analyses of RMS cells exposed to naïve stromal cells identified insulin-like growth factor binding protein 5 (IGFBP5) as the top upregulated gene, with an ability to induce Caspase 3/7 activation and growth arrest. The gene coding for connective tissue growth factor (CTGF) was identified as the major prosurvival factor being downregulated. Analysis of patient cohorts consistently demonstrated an association between IGFBP5, growth arrest specific protein 2 (GAS2), lower disease stage and favorable survival. Altogether, our study identifies a novel anti-tumor growth mechanism with conditionally deregulated genes linked to apoptosis and differentiation in RMS. The results provide support for continued studies on tumor growth-regulatory mechanisms induced by tumor-surrounding stromal cell subsets at primary and metastatic sites in sarcoma. Citation Format: Monika Ehnman, Karim Katkhada, Liu Zhen Meng, Yue Zhang, Binbin Zhao, Shanlin Tong, Aditi Kallai, Arne Östman, Nick Tobin. IGFBP5 is induced by tumor-suppressive naïve stromal cells and regulates GAS2-associated apoptosis in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A039.
Abstract PR006: Multi-modal single-cell profiling of sarcomas from archival tissue reveals mechanisms of resistance to immune checkpoint inhibitors
Authors: Sminu Bose, Blake Caldwell, Amit Dipak Amin, Johannes Melms, Somnath Tagore, Matthew Ingham, Benjamin Izar, Gary K. Schwartz
Journal: Clinical Cancer Research (2022)

Abstract Single-cell genomics is an enabling technology that may inform the molecular underpinnings of drug response and resistance in patient biopsies. These methods are difficult to implement in the study of rare diseases such as sarcomas due to specimen requirements and technical limitations. Here, we evolved novel methods that we recently reported in melanoma (Wang, Fan, et al., bioRxiv, 2022) which enable single-nucleus RNA, T cell receptor (snRNA/TCR-seq), and pool-matched whole-genome sequencing (WGS) from archival frozen sarcoma tissue. This enabled profiling of 75,716 cells and 788 matched TCR clonotypes from six patients with intimal sarcoma (INS) and undifferentiated pleomorphic sarcoma (UPS), including two matched pair samples from pre/post-immune checkpoint inhibitor (ICI). Our analysis revealed substantial transcriptional cancer cell heterogeneity driven by varying copy number alterations (CNAs). In one patient with INS with a complete response to ICI followed by an isolated recurrence, we identified a rare cancer cell clone defined by CNA (confirmed with WGS) and resulting transcriptional outputs that pre-existed and emerged during resistance. Furthermore, in a UPS patient with intrinsic resistance to ICI, we find adequate T cell clonal expansion, activation, and differentiation, suggesting appropriate T cell response to ICI dampened by intrinsic mechanisms of ICI resistance within the cancer cells. Non-negative matrix factorization (NMF) analysis identified cell states associated with either intrinsic or adaptive resistance to ICI that was distinct from resistance to doxorubicin. These observations are consistent with those previously reported from sequential biopsies obtained from KEYNOTE-001 in metastatic melanoma (Wang, Fan, et al., bioRxiv, 2022), which also revealed emergence of pre-existing populations of resistant clones defined by their underlying aneuploidy patterns. Together, these results demonstrate feasibility of implementing single-cell genomics from archival tissue to study sarcoma and propel our understanding of drug resistance. Conceptually, this work suggests that large-scale CNAs may allow us to identify cell sub-populations associated with ICI resistance in sarcoma and in other diseases. Citation Format: Sminu Bose, Blake Caldwell, Amit Dipak Amin, Johannes Melms, Somnath Tagore, Matthew Ingham, Benjamin Izar, Gary K. Schwartz. Multi-modal single-cell profiling of sarcomas from archival tissue reveals mechanisms of resistance to immune checkpoint inhibitors [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR006.
Abstract A002: Dynamic single cell imaging of cancer stem cells and clonality in fusion-negative rhabdomyosarcoma
Authors: Tiffany Eng, Yun Wei, Qian Qin, Chuan Yan, Qiqi Yang, Alexandra Veloso, Karin McCarthy, David Langenau
Journal: Clinical Cancer Research (2022)

Abstract Rhabdomyosarcoma (RMS) accounts for 50% of all soft-tissue childhood sarcomas and is characterized by tumor cells that molecularly and morphologically resemble undifferentiated skeletal muscle. Treatment involves an aggressive regimen of chemotherapy followed by surgical resection and/or radiation therapy. Although survival rates can be as high as 70-90% in low-risk or localized disease, patients with oligoclonal or relapsed disease have extremely poor prognoses. Thus, there is a clinical imperative to identify novel therapeutic targets, particularly ones that could reduce clonality and suppress cancer stem cell self-renewal. Our lab has recently shown that fusion-negative (FN-)RMS contain four dominant tumor cell states: proliferative, ground, mesenchymal cancer stem cells (mCSCs) and differentiated muscle. Importantly, the mCSCs are largely quiescent under normal growth conditions but re-enter the cell cycle to promote tumor growth following stress. This suggests that mCSCs are likely responsible for driving therapy resistance and relapse. Building on our previous successes in live imaging cancer stem cells using transgenic zebrafish models that express fluorophores under control of developmentally restricted muscle promoters, we are now developing similar approaches to drive fluorescent protein expression in human FN-RMS cell lines to trace lineage fate and to witness the division history of mCSCs in real time. Using a combination of CRISPR/Cas9 gene inactivation and these newly developed tools, we are poised to identify new self-renewal pathways by the direct, live-cell imaging of FN-RMS engrafted into optically clear, immune-deficient zebrafish. In addition, we are also using tumor clonality as a surrogate of increased tumor aggression and cancer stem cell potential in the zebrafish RAS-induced RMS model. We have adapted the transgenic zebrafish model of kRASG12D-induced RMS to analyze tumor clonality using multispectral Zebrabow and GESTALT, a CRISPR barcoding technique that tracks cell fate. Using RMS-specific gene expression datasets that are associated with cancer stem cells, we are now screening for genes that elevate tumor clonality, increase tumor penetrance and accelerate tumor growth. Ultimately, by developing these lineage tracing tools in both human RMS cell lines and our transgenic Zebrafish RMS model, we will identify new modulators of the mCSC transcriptional cell states and possible therapeutic targets. Citation Format: Tiffany Eng, Yun Wei, Qian Qin, Chuan Yan, Qiqi Yang, Alexandra Veloso, Karin McCarthy, David Langenau. Dynamic single cell imaging of cancer stem cells and clonality in fusion-negative rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A002.
Abstract A031: Interplay of YAP1, β-catenin and the SS18-SSX fusion protein in synovial sarcoma
Authors: Ilka Isfort, Ruth Berthold, Lorena Heinst, Eva Wardelmann, Marcel Trautmann, Wolfgang Hartmann
Journal: Clinical Cancer Research (2022)

Abstract Introduction: Synovial sarcoma (SySa) is a rare soft-tissue malignancy characterized by a specific chromosomal translocation t(X;18). The resulting chimeric SS18-SSX fusion protein drives SySa pathogenesis by dysregulating gene transcription. As therapeutic targeting of SS18-SSX is notoriously difficult, the identification of SS18-SSX-dependent pathomechanisms may uncover novel molecular vulnerabilities. Since previous functional analyses revealed a connection between SS18-SSX and the activity of the transcriptional co-regulators YAP1/TAZ and β-catenin, this study examined a potential crosstalk between these effectors in SySa. Experimental Procedures: Nuclear abundance of YAP1/TAZ and β-catenin was analyzed by immunohistochemistry in a large cohort of SySa tissue specimens. Two SySa cell lines were employed to modulate YAP1/TAZ/β-catenin transcriptional activity by RNAi-mediated knockdown, small molecule inhibitors, and overexpression vectors in vitro. Changes in transcriptional activity were determined via luciferase reporter assays. As YAP1 and β-catenin showed highest interdependence, co-immunoprecipitation experiments were performed to investigate their interplay with the SS18-SSX fusion protein in SySa cells. Results: Immunohistochemically, a substantial subset of SySa tissue specimens showed concurrent nuclear accumulation of YAP1/TAZ and β-catenin. In vitro, SS18-SSX was found to promote YAP1/TAZ and β-catenin transcriptional activity. RNAi-mediated knockdown of YAP1, TAZ or β-catenin and small molecule inhibitor treatment mutually downregulated TEAD and TCF luciferase reporter activity, while expression of hyperactive variants led to a reciprocal luciferase reporter induction. Finally, co-immunoprecipitation assays demonstrated nuclear co-localization of SS18-SSX with YAP1 and β-catenin in SySa cell lines. Conclusions: This study reveals an interdependency between YAP1 and β-catenin activation and a complex interplay with the SySa-specific SS18-SSX fusion protein. Citation Format: Ilka Isfort, Ruth Berthold, Lorena Heinst, Eva Wardelmann, Marcel Trautmann, Wolfgang Hartmann. Interplay of YAP1, β-catenin and the SS18-SSX fusion protein in synovial sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A031.
Abstract A027: Characterization of WEE1 kinase activity in myxoid liposarcoma
Authors: Lorena Heinst, Ruth Berthold, Ilka Isfort, Svenja Wosnig, Thomas Kindler, Pierre Åman, Eva Wardelmann, Claudia Scholl, Stefan Fröhling, Wolfgang Hartmann, Marcel Trautmann
Journal: Clinical Cancer Research (2022)

Abstract Introduction: Myxoid liposarcomas (MLS), malignant soft tissue tumors of adipocyte origin, are genetically characterized by a chromosomal t(12;16)(q13;p11) translocation encoding the chimeric FUS-DDIT3 fusion gene. The resulting fusion protein drives MLS pathogenesis via (dys-)regulation of oncogenic signaling pathways. Since FUS-DDIT3 is not selectively antagonizable, counteracting the oncogenic effects of FUS-DDIT3 fusion protein represents the most promising strategy to target MLS cells. In this study, we identified cell cycle checkpoint kinase WEE1 as FUS-DDIT3 depending effector and investigated the functional requirement for WEE1 kinase activity in MLS pathogenesis. Experimental Procedures: Characterization of WEE1 expression and kinase activity was performed in multiple MLS cell lines, cell lines derived from other liposarcoma subtypes and a mesenchymal stem cell system. Modulation of WEE1 signaling was carried out by means of small-molecule inhibitor Adavosertib (MK-1775) and RNA interference (RNAi)-mediated depletion, and effects were analyzed in immunoblots, cell proliferation assays and caspase 3/7 activity-based apoptosis assays in vitro. Results: Functional genomic RNAi screening uncovered dependence of FUS-DDIT3-expressing mesenchymal stem cells and MLS cell lines on WEE1 kinase activity. Additional expression analysis revealed increased WEE1 protein levels in MLS cell lines. Moreover, pharmacologic inhibition of WEE1 demonstrated significant reduction of MLS cell viability. Accordingly, functional loss of WEE1 by inhibition or RNAi-mediated depletion was found to induce DNA damage accompanied by unscheduled mitotic entry and cell death via activation of the apoptotic program in MLS cells. Conclusions: Our results identify WEE1 kinase activity as functional liability of FUS-DDIT3 expressing MLS cells and provide first evidence that overactive WEE1 signaling represents a promising target for therapeutic intervention in MLS. Citation Format: Lorena Heinst, Ruth Berthold, Ilka Isfort, Svenja Wosnig, Thomas Kindler, Pierre Åman, Eva Wardelmann, Claudia Scholl, Stefan Fröhling, Wolfgang Hartmann, Marcel Trautmann. Characterization of WEE1 kinase activity in myxoid liposarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A027.
Abstract B013: STEAP1 facilitates iron transport in ewing sarcoma to support mitochondrial activity
Authors: Taras Shyp, Rouhollah Mousavizadeh, Gian Luca Negri, Hai-Feng Zhang, Michael Lizardo, Poul Sorensen
Journal: Clinical Cancer Research (2022)

Abstract Ewing sarcoma (EwS) is a highly aggressive bone-associated tumor of children and young adults with strong propensity to progress and dismal outcome for patients with advanced stages of the disease. EwS is defined by a pathognomonic recurrent potent transcription factor, in 85-90% of cases EWSR1-FLI1. One of the previously described transcriptional targets of EWSR1-FLI1 is six-transmembrane epithelial antigen of the prostate 1 (STEAP1). STEAP1 is a member of the STEAP membrane-bound protein family involved in reduction of iron and copper which is a crucial step for metal transport and overexpressed in various malignancies. However, a precise functional role of STEAP1 in cancers including EwS remains elusive. EwS cell lines with knockout (KO) or knockdown (KD) of STEAP1 were created to perform functional studies for elucidating the functions of STEAP1 in EwS, including transient metal measurements. Additionally, the measurement of functional mitochondrial activity was performed by an extracellular flux analyzer. The activity of the mitochondrial electron transport chain complexes was measured by blue native PAGE. We showed that STEAP1 functions as a metalloreductase and STEAP1 KO cells have lower intracellular iron levels. Furthermore, we discovered that STEAP1 KO cells have significantly lower levels of the mitochondrial labile iron pool. Consequently, EwS cells with STEAP1 KO demonstrated impaired mitochondrial respiration and increased glycolysis rates. Additionally, the functional activity of iron-sulfur containing proteins and the the assembly of subunits of the mitochondrial electron transport chain complexes were decreased. This study is the first to demonstrate in vitro involvement of STEAP1 in transitional metal homeostasis and mitochondrial activity. These discoveries unveil alternative therapeutic strategies for EwS patients such as using compounds that promote an iron-dependent form of cell death, ferroptosis, or drugs that decrease metabolic adaptability. Citation Format: Taras Shyp, Rouhollah Mousavizadeh, Gian Luca Negri, Hai-Feng Zhang, Michael Lizardo, Poul Sorensen. STEAP1 facilitates iron transport in ewing sarcoma to support mitochondrial activity [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B013.